Background: The initiation of methadone, a known effective analgesic for cancer pain, is complex. The existing protocols are often inadequately described; therefore, a classification of literature is needed. We reviewed and classified the recent literature on methadone initiation protocols in cancer patients experiencing severe pain. Objective: To provide a new classification of initiation protocols, based on a critical literature review. Data Sources: The MEDLINE database was searched for articles published until March 25, 2021, using the terms \"cancer pain,\" \"methadone,\" \"methadone introduction,\" or \"methadone initiation.\" The search was limited to human studies, randomized controlled trials (RCTs), other clinical trials, meta-analyses, and case reports. Selected articles were assessed for initiation details (rapid or progressive), administered dose (fixed rescue dose or ad libitum), and dose calculation (fixed or progressive ratios using morphine equivalent daily dose [MEDD] for daily or unitary dose). Results: Twenty-four publications that met our inclusion criteria were analyzed. No large-scale prospective double-blind RCTs with robust design were identified. Most studies assessed relatively small numbers of patients. Eight initiation types were identified, of which three involved seven \"high quality\" studies: \"rapid switch-fixed doses and rescue dose-progressive daily ratio,\" \"progressive switch-fixed dose and rescue dose-progressive daily ratio,\" and \"rapid switch-ad libitum-fixed ratio for unitary dose\" protocols. This classification provides the latest information on methadone initiation protocols. The total daily dose of methadone varied largely across protocols. Conclusion: We recommend a maximal daily methadone dose of 100 mg (3 doses of 30 mg or 5 doses of 20 mg) for MEDD <500 mg, when the two \"ad libitum\" protocols are used. Further clinical research on this topic is warranted.

Opioid rotation from transdermal fentanyl to an alternate opioid is often necessitated in advanced disease, but is fraught with uncertainty due to variable absorption from the patch in end-stage illness and the lack of a clearly established opioid rotation ratio. The manufacturer of transdermal fentanyl provides opioid rotation recommendations only for rotation from the oral morphine equivalent daily dose (MEDD) of opioid to the patch, not in the opposite direction. This is a case report of a single patient with cancer and cachexia admitted to the palliative care unit of a large academic medical centre in Canada. The patient is a 50-year-old female with widely metastatic breast cancer who developed opioid toxicity when maintenance transdermal fentanyl patch therapy (100 μg patch applied every 72 h) was rotated to subcutaneous hydromorphone infusion to improve pain control. Hydromorphone was initiated at a rate of 1 mg/h by continuous infusion based on an opioid rotation ratio for transdermal fentanyl (μg/h):MEDD (mg/day) of 1:2.4. Opioid toxicity eventually resolved with downward titration of hydromorphone to only 30% of the initially estimated equianalgesic dose. This case highlights the need for close follow-up of all patients undergoing opioid rotation from transdermal fentanyl and reinforces the need to reduce the initial dose of the new opioid by 30%-50% of the calculated MEDD, especially when rotating from a high dose of transdermal fentanyl, or if there are factors potentially impairing absorption from the patch such as age, cachexia and weight loss, or if rotation is performed for reasons other than uncontrolled pain.

BACKGROUND: Up to 44% of patients with cancer-related pain require opioid rotation (OR) because of inadequate analgesia or side effects. No consensus exists regarding the most efficacious method for rotation to methadone.
OBJECTIVE: To define the available evidence regarding methods of rotation to methadone and to determine if sufficient evidence exists regarding the superiority of one method.
METHODS: A predefined search strategy, using Medical Subject Headings (MeSH) search terms and keywords combined using Boolean operators, was performed. Study selection was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. Data were extracted, quality of studies assessed, and narrative synthesis undertaken.
RESULTS: A total of 3214 potentially relevant studies were identified. Twenty-five studies were included: 15 retrospective and 10 prospective (n = 1229). One trial compared three-day switch (3DS) and rapid conversion (RC) methods; two, 3DS; 10, RC; nine, ad libitum (AL). Success rates were as follows: 3DS-93%, RC-71.7%, and AL-92.8%. The single clinical trial and retrospective studies demonstrated poorer analgesia and an excess of adverse events (AEs) in the RC group (five dropouts because of AEs) compared with the 3DS group (no severe AEs). Time to stable analgesia was as follows: RC <4.3 days and AL <6 days.
CONCLUSIONS: Evidence identified was mainly from uncontrolled observational studies, making causality difficult to establish. Studies were heterogeneous in methodology and outcome measures. There was a trend toward excess AEs using the RC method, in comparison to the AL and 3DS methods. The methodological quality of the AL studies was low. A direct comparison of AL and 3DS methods would be informative.

When dosed appropriately on carefully chosen patients, methadone can be a very safe and effective choice in managing chronic pain. Many authors have discussed important issues surrounding patient selection, drug interactions, screening for QTc prolongation and monitoring. This article will focus on the dosing dilemma that exists after the patient is deemed an appropriate candidate for methadone and a conversion is necessary from another opioid. Despite many publications dedicated to addressing this challenging topic, there is no consensus on the most appropriate method for converting an opioid regimen to methadone. Given the lack of concrete guidance, clinicians in a community setting are likely to be faced with an increased challenge if there are no available pain specialists to provide clinical support. Common methods for converting morphine to methadone will be reviewed and two clinical patient scenarios used to illustrate the outcomes of applying the methods.

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